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Journal of Medicinal Chemistry Jul 2023Cyclooxygenase-1 and -2 (COX1 and COX2) derived endogenous ligand prostaglandin-E (PGE) triggers several physiological and pathological conditions. It mediates signaling... (Review)
Review
Cyclooxygenase-1 and -2 (COX1 and COX2) derived endogenous ligand prostaglandin-E (PGE) triggers several physiological and pathological conditions. It mediates signaling through four G-protein coupled receptors, EP1, EP2, EP3, and EP4. Among these, EP2 is expressed throughout the body including the brain and uterus. The functional role of EP2 has been extensively studied using EP2 gene knockout mice, cellular models, and selective small molecule agonists and antagonists for this receptor. The efficacy data from in vitro and in vivo animal models indicate that EP2 receptor is a major proinflammatory mediator with deleterious functions in a variety of diseases suggesting a path forward for EP2 inhibitors as the next generation of selective anti-inflammatory and antiproliferative agents. Interestingly in certain diseases, EP2 action is beneficial; therefore, EP2 agonists seem to be clinically useful. Here, we highlight the strengths, weaknesses, opportunities, and potential threats (SWOT analysis) for targeting EP2 receptor for therapeutic development for a variety of unmet clinical needs.
Topics: Animals; Mice; Receptors, Prostaglandin E; Dinoprostone; Cyclooxygenase 2; Drug Discovery; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP4 Subtype
PubMed: 37458373
DOI: 10.1021/acs.jmedchem.3c00655 -
Molecular Therapy : the Journal of the... Dec 2023In vivo apoptosis of human mesenchymal stromal cells (MSCs) plays a critical role in delivering immunomodulation. Yet, caspase activity not only mediates the dying...
In vivo apoptosis of human mesenchymal stromal cells (MSCs) plays a critical role in delivering immunomodulation. Yet, caspase activity not only mediates the dying process but also death-independent functions that may shape the immunogenicity of apoptotic cells. Therefore, a better characterization of the immunological profile of apoptotic MSCs (ApoMSCs) could shed light on their mechanistic action and therapeutic applications. We analyzed the transcriptomes of MSCs undergoing apoptosis and identified several immunomodulatory factors and chemokines dependent on caspase activation following Fas stimulation. The ApoMSC secretome inhibited human T cell proliferation and activation, and chemoattracted monocytes in vitro. Both immunomodulatory activities were dependent on the cyclooxygenase2 (COX2)/prostaglandin E2 (PGE2) axis. To assess the clinical relevance of ApoMSC signature, we used the peripheral blood mononuclear cells (PBMCs) from a cohort of fistulizing Crohn's disease (CD) patients who had undergone MSC treatment (ADMIRE-CD). Compared with healthy donors, MSCs exposed to patients' PBMCs underwent apoptosis and released PGE2 in a caspase-dependent manner. Both PGE2 and apoptosis were significantly associated with clinical responses to MSCs. Our findings identify a new mechanism whereby caspase activation delivers ApoMSC immunosuppression. Remarkably, such molecular signatures could implicate translational tools for predicting patients' clinical responses to MSC therapy in CD.
Topics: Humans; Crohn Disease; Dinoprostone; Leukocytes, Mononuclear; Secretome; Mesenchymal Stem Cells; Immunomodulation; Apoptosis; Caspases
PubMed: 37805713
DOI: 10.1016/j.ymthe.2023.10.004 -
Nature Communications Jan 2024Immune cells must adapt to different environments during the course of an immune response. Here we study the adaptation of CD8 T cells to the intestinal microenvironment...
Immune cells must adapt to different environments during the course of an immune response. Here we study the adaptation of CD8 T cells to the intestinal microenvironment and how this process shapes the establishment of the CD8 T cell pool. CD8 T cells progressively remodel their transcriptome and surface phenotype as they enter the gut wall, and downregulate expression of mitochondrial genes. Human and mouse intestinal CD8 T cells have reduced mitochondrial mass, but maintain a viable energy balance to sustain their function. We find that the intestinal microenvironment is rich in prostaglandin E (PGE), which drives mitochondrial depolarization in CD8 T cells. Consequently, these cells engage autophagy to clear depolarized mitochondria, and enhance glutathione synthesis to scavenge reactive oxygen species (ROS) that result from mitochondrial depolarization. Impairing PGE sensing promotes CD8 T cell accumulation in the gut, while tampering with autophagy and glutathione negatively impacts the T cell pool. Thus, a PGE-autophagy-glutathione axis defines the metabolic adaptation of CD8 T cells to the intestinal microenvironment, to ultimately influence the T cell pool.
Topics: Humans; Animals; Mice; CD8-Positive T-Lymphocytes; Autophagy; Dinoprostone; Genes, Mitochondrial; Glutathione
PubMed: 38200005
DOI: 10.1038/s41467-024-44689-2 -
International Journal of Molecular... Aug 2023The ECM propagates processes in idiopathic pulmonary fibrosis (IPF), leading to progressive lung scarring. We established an IPF-conditioned matrix (IPF-CM) system as a... (Review)
Review
The ECM propagates processes in idiopathic pulmonary fibrosis (IPF), leading to progressive lung scarring. We established an IPF-conditioned matrix (IPF-CM) system as a platform for testing drug candidates. Here, we tested the involvement of a PGE2 and PDE4 inhibitor, Roflumilast, in the IPF-CM system. Primary normal/IPF tissue-derived human lung fibroblasts (N/IPF-HLFs) were cultured on Matrigel and then removed to create the IPF-CM. N-HLFs were exposed to the IPF-CM/N-CM with/without PGE2 (1 nM) and Roflumilast (1 µM) for 24 h. The effect of the IPF-CM on cell phenotype and pro-fibrotic gene expression was tested. In addition, electronic records of 107 patients with up to 15-year follow-up were retrospectively reviewed. Patients were defined as slow/rapid progressors using forced vital capacity (FVC) annual decline. Medication exposure was examined. N-HLFs cultured on IPF-CM were arranged in large aggregates as a result of increased proliferation, migration and differentiation. A PGE2 and Roflumilast combination blocked the large aggregate formation induced by the IPF-CM ( < 0.001) as well as cell migration, proliferation, and pro-fibrotic gene expression. A review of patient records showed that significantly more slow-progressing patients were exposed to NSAIDs ( = 0.003). PGE2/PDE4 signaling may be involved in IPF progression. These findings should be further studied.
Topics: Humans; Dinoprostone; Retrospective Studies; Cells, Cultured; Idiopathic Pulmonary Fibrosis; Lung; Fibroblasts; Fibrosis
PubMed: 37569768
DOI: 10.3390/ijms241512393 -
Clinical Immunology (Orlando, Fla.) Mar 2024Osteoarthritis (OA) is a complex disease characterized by cartilage degeneration and persistent pain. Prostaglandin E2 (PGE2) plays a significant role in OA inflammation... (Review)
Review
Osteoarthritis (OA) is a complex disease characterized by cartilage degeneration and persistent pain. Prostaglandin E2 (PGE2) plays a significant role in OA inflammation and pain. Recent studies have revealed the significant role of PGE2-mediated skeletal interoception in the progression of OA, providing new insights into the pathogenesis and treatment of OA. This aspect also deserves special attention in this review. Additionally, PGE2 is directly involved in pathologic processes including aberrant subchondral bone remodeling, cartilage degeneration, and synovial inflammation. Therefore, celecoxib, a commonly used drug to alleviate inflammatory pain through inhibiting PGE2, serves not only as an analgesic for OA but also as a potential disease-modifying drug. This review provides a comprehensive overview of the discovery history, synthesis and release pathways, and common physiological roles of PGE2. We discuss the roles of PGE2 and celecoxib in OA and pain from skeletal interoception and multiple perspectives. The purpose of this review is to highlight PGE2-mediated skeletal interoception and refresh our understanding of celecoxib in the pathogenesis and treatment of OA.
Topics: Humans; Celecoxib; Dinoprostone; Osteoarthritis; Inflammation; Pain
PubMed: 38262526
DOI: 10.1016/j.clim.2024.109904 -
Journal of Ethnopharmacology Jan 2024Ding-kun-dan (DKD), as one of well-known traditional Chinese medicine (TCM), is considered as an effective prescription to regulate menstruation, benefit Qi and nourish... (Randomized Controlled Trial)
Randomized Controlled Trial
ETHNOPHARMACOLOGICAL RELEVANCE
Ding-kun-dan (DKD), as one of well-known traditional Chinese medicine (TCM), is considered as an effective prescription to regulate menstruation, benefit Qi and nourish the blood. Previous studies had showed that DKD could improve sex hormone levels, insulin resistance, metabolism abnormalities and regulate immunity in animal models with polycystic ovary syndrome or endometriosis, however, little study conducted to reveal its clinical efficacy in Primary Dysmenorrhea (PD).
AIM OF THE STUDY
To compare the effect of Ding-kun-dan (DKD) with Marvelon on relief of symptoms and change of serum pain-related factors in patients with primary dysmenorrhea.
MATERIALS AND METHOD
136 patients with primary dysmenorrhea were randomly assigned to the DKD group (n = 73, take one tablet per day from 5th day of the menstrual cycle for 10 days every 28 days) and the Marvelon group (n = 63, take one tablet per day from 5th day of the menstrual cycle for 21 days every 28 days), the therapeutic effects were analyzed through evaluating the change of VAS scores, CMSS scores and the level of PGF, PGE, PGF/PGE and NO during the 12 weeks intervention.
RESULTS
Both DKD and Marvelon could effectively relief pain and other associated symptoms at each visit (Baseline, 4 week, 8 week and 12 week). Although Marvelon was significantly superior to DKD in reducing VAS scores, the total CMSS, CMSS severity and duration scores at each posttreatment follow-up (P < 0.01), VAS scores in the DKD group decreased significantly over time while scores in the COC group only dropped rapidly after the first two months of treatment. Efficacy gap between two interventions continuously narrowed over time and the efficacy of DKD became non-inferior at the 12 week compared to that of Marvelon (the difference between groups, - 0.78%; 95% confidence interval (CI), -13.67%-12.75%; non-inferiority margin, 15%). DKD group had better efficacy on mild pain compared to that of the COC group with no statistical difference (75% VS 61.9%, P > 0.05). DKD and Marvelon could effectively reduce PGF, PGE and higher PGF/PGE in patients with PD. There was no statistical difference in the level of PGF, PGE, PGF/PGE and NO between DKD and Marvelon group at each follow-up. No serious adverse effect was observed.
CONCLUSION
Ding-kun-dan is another available, effective and safe method for patients with primary dysmenorrhea to choose, especially for those who are suffered from mild pain and/or contraindicated to hormonal agents.
Topics: Female; Humans; Desogestrel; Dinoprostone; Double-Blind Method; Dysmenorrhea; Endometriosis; Medicine, Chinese Traditional; Prospective Studies
PubMed: 37517569
DOI: 10.1016/j.jep.2023.116975 -
American Journal of Obstetrics and... Mar 2024This review assessed the efficacy and safety of pharmacologic agents (prostaglandins, oxytocin, mifepristone, hyaluronidase, and nitric oxide donors) and mechanical... (Review)
Review
This review assessed the efficacy and safety of pharmacologic agents (prostaglandins, oxytocin, mifepristone, hyaluronidase, and nitric oxide donors) and mechanical methods (single- and double-balloon catheters, laminaria, membrane stripping, and amniotomy) and those generally considered under the rubric of complementary medicine (castor oil, nipple stimulation, sexual intercourse, herbal medicine, and acupuncture). A substantial body of published reports, including 2 large network meta-analyses, support the safety and efficacy of misoprostol (PGE1) when used for cervical ripening and labor induction. Misoprostol administered vaginally at doses of 50 μg has the highest probability of achieving vaginal delivery within 24 hours. Regardless of dosing, route, and schedule of administration, when used for cervical ripening and labor induction, prostaglandin E2 seems to have similar efficacy in decreasing cesarean delivery rates. Globally, although oxytocin represents the most widely used pharmacologic agent for labor induction, its effectiveness is highly dependent on parity and cervical status. Oxytocin is more effective than expectant management in inducing labor, and the efficacy of oxytocin is enhanced when combined with amniotomy. However, prostaglandins administered vaginally or intracervically are more effective in inducing labor than oxytocin. A single 200-mg oral tablet of mifepristone seems to represent the lowest effective dose for cervical ripening. The bulk of the literature assessing relaxin suggests this agent has limited benefit when used for this indication. Although intracervical injection of hyaluronidase may cause cervical ripening, the need for intracervical administration has limited the use of this agent. Concerning the vaginal administration of nitric oxide donors, including isosorbide mononitrate, isosorbide, nitroglycerin, and sodium nitroprusside, the higher incidence of side effects with these agents has limited their use. A synthetic hygroscopic cervical dilator has been found to be effective for preinduction cervical ripening. Although a pharmacologic agent may be administered after the use of the synthetic hygroscopic dilator, in an attempt to reduce the interval to vaginal delivery, concomitant use of mechanical and pharmacologic methods is being explored. Combining the use of a single-balloon catheter with dinoprostone, misoprostol, or oxytocin enhances the efficacy of these pharmacologic agents in cervical ripening and labor induction. The efficacy of single- and double-balloon catheters in cervical ripening and labor induction seems similar. To date, the combination of misoprostol with an intracervical catheter seems to be the best approach when balancing delivery times with safety. Although complementary methods are occasionally used by patients, given the lack of data documenting their efficacy and safety, these methods are rarely used in hospital settings.
Topics: Female; Humans; Pregnancy; Abortifacient Agents, Nonsteroidal; Cervical Ripening; Dinoprostone; Hyaluronoglucosaminidase; Labor, Induced; Mifepristone; Misoprostol; Nitric Oxide Donors; Oxytocics; Oxytocin
PubMed: 38462252
DOI: 10.1016/j.ajog.2023.02.009 -
Nature Communications Dec 2023The lipid prostaglandin E (PGE) mediates inflammatory pain by activating G protein-coupled receptors, including the prostaglandin E2 receptor 4 (EP4R). Nonsteroidal...
The lipid prostaglandin E (PGE) mediates inflammatory pain by activating G protein-coupled receptors, including the prostaglandin E2 receptor 4 (EP4R). Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce nociception by inhibiting prostaglandin synthesis, however, the disruption of upstream prostanoid biosynthesis can lead to pleiotropic effects including gastrointestinal bleeding and cardiac complications. In contrast, by acting downstream, EP4R antagonists may act specifically as anti-inflammatory agents and, to date, no selective EP4R antagonists have been approved for human use. In this work, seeking to diversify EP4R antagonist scaffolds, we computationally dock over 400 million compounds against an EP4R crystal structure and experimentally validate 71 highly ranked, de novo synthesized molecules. Further, we show how structure-based optimization of initial docking hits identifies a potent and selective antagonist with 16 nanomolar potency. Finally, we demonstrate favorable pharmacokinetics for the discovered compound as well as anti-allodynic and anti-inflammatory activity in several preclinical pain models in mice.
Topics: Humans; Mice; Animals; Dinoprostone; Receptors, Prostaglandin; Phagocytosis; Anti-Inflammatory Agents; Pain; Anti-Inflammatory Agents, Non-Steroidal
PubMed: 38057319
DOI: 10.1038/s41467-023-43506-6 -
Biochemical Pharmacology Nov 2023This review article summarizes the role of prostaglandin E (PGE) and its receptors (EP1-EP4) as it relates to the inflammatory cardiomyopathy, myocarditis. During the... (Review)
Review
This review article summarizes the role of prostaglandin E (PGE) and its receptors (EP1-EP4) as it relates to the inflammatory cardiomyopathy, myocarditis. During the COVID-19 pandemic, the onset of myocarditis in a subset of patients prompted a debate on the use of nonsteroidal anti-inflammatory drugs (NSAIDs), like ibuprofen, which act to inhibit the actions of prostaglandins. This review aims to further understanding of the role of PGE in the pathogenesis or protection of the myocardium in myocarditis. Inflammatory cardiomyopathies encompass a broad spectrum of disorders, all characterized by cardiac inflammation. Therefore, for the purpose of this review, the authors have placed particular emphasis on etiologies of myocarditis where effects of PGE have been documented.
Topics: Humans; Myocarditis; Pandemics; Receptors, Prostaglandin E, EP4 Subtype; Dinoprostone; Prostaglandins
PubMed: 37722627
DOI: 10.1016/j.bcp.2023.115813 -
PloS One 2024The Maternal and Perinatal Death Surveillance and Response (MPDSR) was introduced in Kenya in 2016 and implemented at Kiambu Level 5 Hospital (KL5H) three years later in... (Comparative Study)
Comparative Study
BACKGROUND
The Maternal and Perinatal Death Surveillance and Response (MPDSR) was introduced in Kenya in 2016 and implemented at Kiambu Level 5 Hospital (KL5H) three years later in 2019. During a routine MPDSR meeting at KL5H, committee members identified a possible link between the off-label use of 200mcg misoprostol tablets divided eight times to achieve the necessary dose for labour induction (25mcg) and maternal deaths. Following this, an administrative decision was made to switch from misoprostol to dinoprostone for the induction of labour in June of 2019. This study aimed to assess the overall impact of MPDSR as well as the effect of replacing misoprostol with dinoprostone on uterine rupture, maternal and neonatal deaths at KL5H.
METHODS
We conducted a retrospective cohort study of women who gave birth at KL5H between January 2018 and December 2020. We defined the pre-intervention period as January 2018-June 2019, and the intervention period as July 2019-December 2020. We randomly selected the records of 411 mothers, 167 from the pre-intervention period and 208 from the intervention period, all of whom were induced. We used Bayes-Poisson Generalised Linear Models to fit the risk of uterine rupture, maternal and perinatal death. 12 semi-structured key person questionnaires was used to describe staff perspectives regarding the switch from misoprostol to dinoprostone. Inductive and deductive data analysis was done to capture the salient emerging themes.
RESULTS
We reviewed 411 patient records and carried out 12 key informant interviews. Mothers induced with misoprostol (IRR = 3.89; CI = 0.21-71.6) had an increased risk of death while mothers were less likely to die if they were induced with dinoprostone (IRR = 0.23; CI = 0.01-7.12) or had uterine rupture (IRR = 0.56; CI = 0.02-18.2). The risk of dying during childbearing increased during Jul 2019-Dec 2020 (IRR = 5.43, CI = 0.68-43.2) when the MPDSR activities were strengthened. Induction of labour (IRR = 1.01; CI = 0.06-17.1) had no effect on the risk of dying from childbirth in our setting. The qualitative results exposed that maternity unit staff preferred dinoprostone to misoprostol as it was thought to be more effective (fewer failed inductions) and safer, regardless of being more expensive compared to misoprostol.
CONCLUSION
While the period immediately following the implementation of MPDSR at KL5H was associated with an increased risk of death, the switch to dinoprostone for labour induction was associated with a lower risk of maternal and perinatal death. The use of dinoprostone, however, was linked to an increased risk of uterine rupture, possibly attributed to reduced labour monitoring given that staff held the belief that it is inherently safer than misoprostol. Consequently, even though the changeover was warranted, further investigation is needed to determine the reasons behind the rise in maternal mortalities, even though the MPDSR framework appeared to have been put in place to quell such an increase.
Topics: Humans; Misoprostol; Female; Labor, Induced; Pregnancy; Retrospective Studies; Adult; Dinoprostone; Oxytocics; Uterine Rupture; Infant, Newborn; Young Adult; Perinatal Death; Maternal Mortality
PubMed: 38820427
DOI: 10.1371/journal.pone.0304631